This revised renewal application, consisting of 5 scientific components and 2 core facilities, will define the mechanisms involved in thrombo-atherosclerosis. Through continued active collaborations, we will test the hypothesis that soluble mediators (e.g. nitrogen oxides, reactive oxygen species, growth factors) regulate vascular cell reactivity. Our aims focus on interactions between hematologic and vascular cells to define the: effects of fluid-phase and cell-associated thromboregulators (ectoADPase/CD39;nitric oxide (NO);eicosanoids on vascular and blood cell reactivity;regulation of the annexin 2 stress responses to vascular perturbation;growth factor regulation of adaptive vascular remodeling in neo-angiogenesis;subcellular regulation of eNOS activity in endothelial cells;and, the modulation of cyclooxygenase by nitrogen oxides including their impact on atherogenesis. Through the support of this PPG during the last 5 years, we discovered: 1) the ecto ADPase is the major thromboregulator of the vasculature, 2) annexin 2 is a key regulator of fibrin homeostasis and vascular remodeling, 3) neurotropins are critical modulators of angiogenesis and atherogenesis, 4) the role of pterin oxidation and structural elements of eNOS which regulate NO and peroxynitrite production, and 5) NO and peroxynitrite alter cyclooxygenase structure which impacts on inflammation. In this revised proposal, we carefully addressed each of the Reviewers specific concerns by providing new data or designing new experiments per their request. The SRC felt that the strengths of the Program outweigh any weaknesses, and that the program itself consisted of outstanding project leaders, who designed novel experiments, making it a program of significance. This program takes advantage of the complementary research expertise of our vascular biology group to promote continued synergistic interactions. Our on-going collaborative efforts, where our PPG Vascular Biology group has published over 90 research papers during the past 5 years, coupled with our major scientific discoveries, underscores the success of this program. As a testament to our achievements, Cornell Medical College established a Center of Vascular Biology headed by Dr. David Hajjar. Institutional funds (>$5.0 million) have been designated for capital improvements, equipment, and faculty development to support this program.